Type-1 Steroid Hormone Expression Regulation
Overview Steroid hormones have the ability to regulate gene expression through binding at specific receptors called nuclear receptors, which then bind specific sequences of DNA called hormone response elements (HRE) and modulate polymerase activity. This can happen through two main mechanisms attributed to two different types of receptor (type I and II) with different classes, I-VI, which are mainly separated by differences in homology or binding site. These receptors can either activate or repress transcription through their recruitment of coactivators or corepressors depending on the complex in question. The type I receptor is thought to be the "classical" model of hormone receptor binding and regulation. D. Manglesdorf et al. (Dec. 1998). The nuclear receptor superfamily: the second decade. Cell.83(6):835-9. [http://www.ncbi.nlm.nih.gov/pubmed/8521507 PubMed]A. Aranda and A. Pascual. (July 2001) Nuclear hormone receptors and gene expression. Physiol Rev. 81(3):1269-304. [http://www.ncbi.nlm.nih.gov/pubmed/11427696 PubMed] Steroid Hormones The type-I mechanism typically deals with adrenal steroid hormones. Steroid hormones are a class of hydrophobic, membrane permeable molecules that are secreted in response to a physiological stimulus. ] These stimuli can range from stress to dietary responses, which cause the steroids to be synthesized and secreted from the adrenal cortex. The responses mediated by these hormones are typicallly in need of regluation due their effects being either linked to breakdown or synthesis of important physiological compounds, with a lack of inhibition of either action being highly detrimental to organisms. Some examples of steroids that use this type of receptor are glucocorticoids, androgens, and estrogensD. Voet, J. Voet, C. Pratt (2008) 3rd Edition. New Jersey. John Wiley & Sons. Print. '''Examples of Steroid Hormones''' '''Glucocorticoids''': Primarily used to control inflammation through inhibiting initial steps in immune response stimulated by inflammation or infection, with excessive response typically being destructive to healthy tissues.A. Couthino and K Chapman. (March 2011)The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol. 335(1): 2–13.[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3047790/ PubMed] In addition, glucocorticoids can control fatty acid, carbohydrate, and protein metabolism, misregulation of which can cause a wide variety of detrimental effects including poor glucose utilization and mobilization as well as abnormal fat deposition.A. Rose, A. Vegiopoulos, S. Herzig. (Oct. 2010)Role of glucocorticoids and the glucocorticoid receptor in metabolism: insights from genetic manipulations.J Steroid Biochem Mol Biol. 122(1-3):10-20 [http://www.ncbi.nlm.nih.gov/pubmed/20170729 PubMed] '''Androgens''': Androgens are typically developmental or stress related hormones that stimulate growth upon release. Primarily important in males (testosterone, for example) and as estrogen precursors in females, androgens are related to muscle growth, fat level control, and mood regulation. Misregulation of androgens can lead to developmental issues (especially in the testes), muscle growth issues, fertility issues, and mood changes.K. Cox et al. (2014) Novel Associations in Disorders of Sex Development: Findings From the I-DSD Registry, J Clin Endocrinol Metab. 99(2): E348–E355. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955252/ PubMed]C. Wang et al. (2004) Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab. 89(5):2085-98. [http://www.ncbi.nlm.nih.gov/pubmed/15126525 PubMed] '''Estrogens''': Primarily important in females for development, Estrogens regulate mood, fat deposition and reproduction. The most serious consequence of abnormal estrogen levels is a higher chance of breast cancer due to a higher level of breast cell proliferation. J. Yager (2000)Endogenous estrogens as carcinogens through metabolic activation.J Natl Cancer Inst Monogr.(27):67-73. [http://www.ncbi.nlm.nih.gov/pubmed/?term=10963620 PubMed] '''Mineralocorticoids''': Typically responsible for salt (sodium and potassium) excretion, as well as water excretion, from cells. Defects can lead to poor regulation of salt ions, resulting in edema and potential paralysis. Type I Mechanism Type 1 mechanisms for steroid hormones involve the receptor existing as a free floating, inactive cytoplasmic complex with a heat shock protein (HSP) (typically HSP 56, 70, or 90). Upon passage through the membrane by the steroid hormone, it will bind to the receptor's ligand binding site and cause the HSP to dissociate. Upon dissociation from the HSP, newly formed monomeric complexes can then bind another monomer to form a dimeric complex consisting of 2 hormone-receptor complexes. This complex then becomes activated , moving into the nucleus from the cytosol and binding to the HRE of a DNA sequence, recruiting a coactivator to upregulate or downregulate gene expression.R. Evans. (1988) THe steroid and thyroid hormone superfamily Science. 240(4854):889-95. [http://www.ncbi.nlm.nih.gov/pubmed/3283939 PubMed]These coactivators can bind to the receptor in two places, called the activation function domains, located on the A/B domain and near the C-terminus after binding the hormone ligand. A common example of a co-activator is SRC-1 which can increase gene transcrption through histone and chromatin remodeling, allowing for better access to the DNA, or by directly interacting with polymerase proteins to increase transcription.S. Onate et al. (1998)The steroid receptor coactivator-1 contains multiple receptor interacting and activation domains that cooperatively enhance the activation function 1 (AF1) and AF2 domains of steroid receptors. J Biol Chem. 273(20):12101-8.[http://www.ncbi.nlm.nih.gov/pubmed/9575154 PubMed] Some Gene Targets of Steroid Hormones * CREBBP (Cortisol)-CREB Binding Protein , a coactivator of cyclic-AMP response element binding protein (CREB), typically involved in modulating metabolism during stress and fasting. B. Jenkins, C. Pullen, B. Darimont. (2001) Novel glucocorticoid receptor coactivator effector mechanisms. Trends Endocrinol Metab. 12(3):122-6. [http://www.ncbi.nlm.nih.gov/pubmed?cmd=Search&term=11306337 PubMed] * GLUT3 (Testosterone)- Glucose Transporter, increases glucose available to skeletal muscle during stress responses.M. Haren et al. (2011) Testosterone modulates gene expression pathways regulating nutrient accumulation, glucose metabolism and protein turnover in mouse skeletal muscle. Int J Androl. 34(1):55-68 [http://www.ncbi.nlm.nih.gov/pubmed/20403060 PubMed] * TPD52L1 (Estrogen)-Tumor Protein D52, thought to increase cell proliferation. A. Charpentier et al. (2000)Effects of estrogen on global gene expression: identification of novel targets of estrogen action. Cancer Res. 60(21):5977-83. [http://www.ncbi.nlm.nih.gov/pubmed/11085516 PubMed] Other Diseases Related to Steroid Secretion '''Addison's Disease''': Characterized by low secretion of cortisol and aldosterone (glucocorticoid and mineralocorticoid), effectively producing poor immune responses and tissue repair due to the lower levels of these important hormones in the body. Typically this disease manifests after the adrenal cortex has been damaged, making hormone secretion slow down. Treatments may vary but are typically introduction of common missing hormones based on symptoms presented.Addison Disease. Medline Plus. Nov. 7, 2013. [http://www.nlm.nih.gov/medlineplus/ency/article/000378.htm Link] '''Cushing's Syndrome: '''Characterized by an overproduction of''' '''cortisol, this disease typically results in abnormal fat deposition, as well as other more complicated symptoms like diabetes or slow healing of wounds, due to the rise in corticoids and cortisol. Typically this disease is in response to a patient being on corticosteroid treatments, leading to an overabundance, but can also be caused by glandular issues as well. The most common treatment are the restriction of corticosteroid use, or in extreme cases, surgery to lower cortisol production.Cushing Syndrome. Mayo Clinic. March 28, 2013. [http://www.mayoclinic.org/diseases-conditions/cushing-syndrome/basics/definition/con-20032115 Link] References